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Carcinogenesis Advance Access originally published online on December 29, 2005
Carcinogenesis 2006 27(4):864-873; doi:10.1093/carcin/bgi321
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Essential roles of PI-3K/Akt/IKKß/NF{kappa}B pathway in cyclin D1 induction by arsenite in JB6 Cl41 cells

Weiming Ouyang 1, Jingxia Li 1, Qian Ma and Chuanshu Huang *

Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA

* To whom correspondence should be addressed. Tel: +1 845 731 3519; Fax: +1 845 351 2320; Email: chuanshu{at}env.med.nyu.edu

Skin is a major target of carcinogenic trivalent arsenic (arsenite, As3+). It has been thought that cell proliferation is one of the central events involved in the carcinogenic effect of arsenite. Cyclin D1, a nuclear protein playing a pivotal role in cell proliferation and cell cycle transition from G1 to S phases, has been reported to be induced in human fibroblast by arsenite via uncertain molecular mechanisms. In the present study, the potential roles of PI-3K/Akt/IKKß/NF{kappa}B signal pathway in cyclin D1 induction by arsenite were addressed in mouse epidermal Cl41 cells. We found that exposure of Cl41 cells to arsenite was able to induce cell proliferation, activate PI-3K->Akt/p70S6k signal pathway and increase cyclin D1 expression at both transcription and protein levels. Pre-treatment of Cl41 cells with PI-3K inhibitor, wortmannin, significantly inhibited the phosphorylation of Akt and p70S6k and thereby dramatically impaired the cyclin D1 induction by arsenite, implicating the importance of the PI-3K signal pathway in the cyclin D1 induction by arsenite. Furthermore, inhibition of PI-3K/Akt by overexpression of {Delta}p85 or DN-Akt blocked arsenite-induced IKK phosphorylation, I{kappa}B{alpha} degradation and cyclin D1 expression, indicating that IKK/NF{kappa}B is the downstream transducer of arsenite-triggered PI-3K/Akt cascade. Moreover, inhibition of IKKß/NF{kappa}B signal pathway by overexpression of its dominant negative mutant, IKKß-KM, also significantly blocked arsenite-induced cyclin D1 expression. Overall, arsenite exposure triggered PI-3K/Akt/IKKß/NF{kappa}B signal cascade which in turn plays essential roles in inducing cyclin D1 expression.


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